ABSTRACT Breast cancer affects African-American women at a lower frequency than white women, yet progression of the tumor and mortality from the disease is higher in the minority population. This discordance highlights a major health disparity in the United States (US) that is poorly understood. The overwhelming majority of studies aimed at understanding this disparity have focused on social and economic differences between African- American women and whites, which clearly have significant health consequences across a spectrum of diseases, including cancer. On the contrary, there is a paucity of studies on the potential role heterogeneity in tumor biology plays in the health disparity in breast cancer. Tumor suppressor genes, such as adhesion molecules tethered at sites of cell-contact intimately influence cancer progression, and are therefore, candidate molecules for understanding this disparity. Despite this significance, no study has hitherto examined the contribution of cell-cell adhesion molecules to the aggressive tumor growth in African American women with breast cancer. Indeed, the identity of specific molecules and cognate mechanisms that influence tumor growth in breast cancer are poorly understood, and are therefore the focus of this application. Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a member of the immunoglobulin super family. The Project Leader's laboratory has recently localized ALCAM to sites of cell-cell contact in epithelial tissues. The co-investigator and the PI recently showed that reduced expression of ALCAM mRNA is a prognostic marker of breast cancer. Two recent studies have conflicting data on the impact of ALCAM protein regulation on breast cancer, with one study showing reduced protein expression, whereas the other found cytoplasmic ALCAM staining to be the key determinant of poor prognosis. Despite these differences, there is a consensus that loss of ALCAM function due to reduced expression or mislocation is a poor prognostic indicator in breast cancer. It is therefore critically important to identify the precise type of ALCAM dysfunction that contributes to tumor development in breast cancer. In particular, there is a great need for hypothesis driven studies, as well as additional observational studies involving a wider patient population. This application offers both types of investigations. Importantly, for the first time the proposed research includes African American women, who do worse with breast cancer, but have hitherto not been included in studies aimed at addressing ALCAM's role in breast cancer. We have cloned the ALCAM promoter and identified multiple cis regulatory DMA sequences that control promoter activity. Further studies have identified a protein phosphatases (PP5) that negatively regulates ALCAM expression in MCF-7 breast cancer cells. Over-expression of PP5 reduced ALCAM expression and caused MCF-7 cells to form larger tumors in nude mice than parental MCF-7 cells. Based on these preliminary findings we will explore the OVERALL HYPOTHESIS that "Loss of Function of ALCAM Causes an Aggressive Tumor Phenotype in Breast Cancer that may contribute to Poor Survival in African- American Women with Breast Cancer" Three Specific Aims test the related hypothesis that: [1] ALCAM gene expression is suppressed in breast cancer [2] PP5 promotes breast cancer tumor growth, in part by, suppressing ALCAM expression [3] Loss of function of ALCAM contributes to aggressive tumor biology in African-American women with breast cancer This application is timely and intimately linked to the research activities of the University's EXPORT Center for Health Disparities and Minority Health. It fulfils the urgent need to investigate heterogeneity of breast cancer tumor biology in African American and white women, and it fulfills an innovative attempt to advance our understanding of ALCAM's role in breast cancer tumor biology.